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A tandem synthesis of (±)-euphococcinine and (±)-adaline
Tmah
Lerrm.
Vol. 36. No. 49. pp 9047.9050, 1995 Elsevier Science Ltd Pnnted in Great Britain 004l~-4039/95 $9.50+0.00
0030-4039~95 10 190% I
A Tandem Synthesis of (k):)-Euphococcinine and (zk))-Adaline Edwin C. Davison and Andrew B. Holmes* l~n~venily Chemical Laboratory. Lensfield Road CAMBRIDGE CB2 IEW, U.K. SmithKline
Beecham
Pharmaceuticals.
Ian New Frontiers
T. Forbes Science Park, Third Avenue,
HARLOW
CM19
5AW. U.K.
Intramolecular hydroxylamine-alkyne cyclisation of the hydroxylamines 8 and 9 afforded sixmembered cyclic nitrones which without isolation undcrwcnt a tandem irmamolecular dipolar cycloaddition to produce the uicyclic isoxazolidines 6 and 7 respectively. These were converted in two steps into the ladybird defence alkaloids (f)-euphoccccinine 4 and (+)-adaline 5
Abstract:
We have previously
described the hydroxylamine-alkyne
cyclisation
of 1 to give the cyclic nitrone 2,
followed by tandem intramolecular dipolar cycloaddition to afford the tricyclic adduct 3 (R = Me) (Schemel),l and we have explored the scope of this cyclisation as a general route to five-, six- and seven-membered cyclic nitrones.? In this Letter the tandem methodology is applied to a concise synthesis of the ladybird defence alkaloids adaline 4 and euphocococcinine 5. TMS
0.
1
Scheme 1 &agenrs
und
Euphococcimnc
2 coditions
: (a) Toluene,
reflux.
I3
3
h (83%)
4 was first isolated from a small sea-coast plant, Euphorbia
aroto Forst.,3 but has
subsequently been found as part of the chemical defence system of both the Australian mealybug ladybird, Cryptdaemus montrouzirri,4 and the Mexican bean beetle. Epilachna varivestis.5 The enantiomerically related alkaloid, adaline 5, also acts as part of the defence system of the European ladybird, Ad& bipunctata, and also has been isolated from Quadrimacukutu Scopoli and P~nrhrrinu L.6 Both alkaloids are proven feeding deterrents to spiders and ants.
9048
A variety of approaches to these alkaloids have been described. 7.8 Both euphococcinine
4 and adaline 5
could be synthesised in racemic form via the tricyclic systems of the type 6 and 7, which could be easily prepared from acyclic hydroxylamines such as 8 and 9 (Scheme 2).
R
R >
Scheme
8; R'= TMS 9; R’ = C4H,
6;R=Me 7; R=C,H,,
(f)-4; R = lie (+)-5; R = C,H,, 2
5Hexyn-l-01 10 was chosen as the starting material for both the natural products. Silylation of the terminal alkyne and the primary alcohol, followed by cleavage of the trimethylsilyl ether gave the alcohol 11 for euphococcinine. Alternatively, formation of 1-tetrahydropyranyloxy-5-hexyne 12, followed by alkylation using butyllithium, tetramethylethylenediamine (TMEDA) and iodobutane, and acetal cleavage afforded the alcohol 13 which served as the key starting compound for adaline.
\%/-OH
TMsboH
a
10
11
c OTHP
F
OH
12 13 Scheme 3 Reagents and conditions: (a) (i) nBuLi, (ii) TMSCl, (iii) HCl aqueous (76%); (b) (i) Dihydropyran, Amberlyst-15 resin, (ii) nBuLi, TMEDA, followed by BuBr (60%); (c) Amberlyst-15. MeOH. Swern oxidation’ of the alcohols 11 and 13 gave the aldehydes 14 and 15 in good yield (Scheme 4). Addition of ally1 magnesium bromide gave the secondary alcohols 16 and 17. Oxidation of the alcohols using C~O~-HOAC,~~ followed by treatment with hydroxylamine hydrochloride in pyridine-ethanol gave the oximes 18 and 19. These were reduced to the corresponding hydroxylamines using sodium cyanoborohydride at pH 3-4. The hydroxylamines were heated to reflux in toluene for 9-12 hours. The resulting nitrones were not isolated, but underwent in situ intramolecu1a.r dipolar cycloaddition to afford the tricyclic adducts 6 and 7.
9049
R’LOH
a
) R’k~O
11; R’=TMS 13; R’=Bu
b 14; R’=TMS 15; R’ = Bu
18; R’=TMS 19; R’=Bu
6;R’=H 7; R’ = Bu
Scheme 4 Reagents rind conditions : (a) Oxalyl chloride, DMSO, Et3N (80-90%); (b) CH2=CHCH2MgBr, ether (70-81%); (c) (i) Cr03, HOAc, (ii) NH2OH.HCl. Py-EtOH (5866%); (d) NaCNBH3. MeOH, pH 3-4; (e) Toluene, reflux, 9 h (7 1.76%). The tricyclic systems were formed in good yield, allowing completion of the syntheses according to the route used by G&singer8 for adaline. Reductive cleavage of the N-O bond, using Raney-nickel and hydrogen, afforded the bicyclic alcohols 20 and 21 in excellent yield. Oxidation of the alcohols with pyridinium chlorochromate gave the required alkaloids (+)-euphococcinine 1 and (+)-adaline 2 respectively, in good yields (Scheme 5).11
R’ dN e H* b-H* a
J
w
HO
6; R’ = H 7; R’ = Bu
Scheme 5 Reagents and conditions:
20; I?‘= H 21; R’= Bu
(a) Raney-Ni. Hz. 90 min (93-96%);
(9-4; (f)-5;
R’ = H R’ = Bu
(b) PCC. CH2Cl2 (70-72%)
Acknowledgements We thank the E.P.S.R.C. for financial support and SmithKline Beechatn Pharmaceuticals for a CASE (ECD). We thank Dr. J. Ballantine (EPSRC Mass Spectrometry Service) for providing mass spectra and Pfizer Central Research (Sandwich) for financial support.
award
9050
References 1. Holmes, A.B.; Smith, A.L.; Williams, S.F.; Hughes, L.R.; Lidert, Z.; Switbenbank, C. J. Org. Chem., 1991, 56. 1393-1405. Fox, M.E.; Holmes. A.B.; Forbes, I.T.; Thompson, M. J. Chem. Sot. Perkin. Trans. 1 1994, 33792. 3395. 3. Hart, N.K.; Johns, S.R.; Lamherton. J.A. AUG. J. Chem. 1967.20, 561-563. Brown, W.V.; Moore, B.P. Ausr. J. Chem. 1982.35. 1255-1261. 4. Eisner, T.; Goetz. M.; Aneshansley, D.; Fetstandig-Arnold, G.; Meinwald, J. Experienta 198642. 2045. 201. 6. 7.
8. 9. 10. 11.
Tursch, B.; Braekman. J.C.; Daloze. D.; Hootele, C.; Losman, D.; Karlsson, R.; Pasteels, J.M. Tetrahedron Let?. 1973. 201-202. Alder. K.; Betzing, H.; Kuth. R.; Dortman, H.H. Liehigs Ann. Chem. 1959,620, 73-87. Hill, R.K.; Renbaum, L.A. Tetrahedron 1982. 3X. 1959- 1963. Gnecco Medina, D.H.; Grierson, D.S.; Husson, H.-P. Tetrahedron Lett. 1983,24, 2099-2102. Yue, C.; Royer, J.; Husson, H.-P. J. Org. Chem. 1992, 57, 4211-4214. G&singer. E.; Witkop, B. Monatsh. Chem. 1980, 111, 803-811. Mancuso. A.J.: Huang, S.L.; Swern, D. J. Org. Chem. 1978,43, 2480-2482. Price, C.C.; Karabinos, J.V. J. Am. C/rem. Sot. 1940.62, 1159-1161. All new compounds exhibited spectroscopic and microanalytical/high resolution mass spectral data in accord with the assigned structure. Selected spectroscopic data: lsoxazolidine 6: 611 (250 MHz, CDCl$ 4.64 (lH, t, J 5 Hz), 3.50-3.39 (lH, m), 1.92-1.79 (lH, m), 1.70-1.50 (4H. m). 1.44-1.22 (5H, m), 1.05 (3H, s); 6~ (100 MHz, CDCl3) 81.7 (d). 65.1 (s), 61.1 (d), 43.2 (t), 35.9 (t), 33.3 (t), 31.4 (q), 25.5 (t), 14.4 (t); m/z (EI) 153 (MH+. 1X’+), 126 (30), 105 (29). 79 (76). 73 (74), 55 (lOO), 41 (98); [Found: M+H+ 154.1232 (EI). CgH15NO requires M+H 154.12321; Euphococcinine 4: ?iB (400 MHz, CDC13) 3.72-3.68 (IH, m), 2.5X (lH, dd, I16, 6.6 Hz), 2.37 (lH, dd, J 16, 2.5 HZ), 2.33 (lH, d, J 16 HZ), 2.23 (lH, d, J 16Hz), 1.76-1.42 (7H. m). 1.19 (3H, s); 6~ (l(H) MHz, CDCl$ 210.5 (s), 53.2 (t), 52.5 (s), 49.8 Cd), 45.9 (0. 38.6 (t), 31.3 (q), 30.9 (q), 17.9 (t); m/i (El) 153 (M+* SC/c), 110 (44), 96 (52), 82 (41), 55 (26), 42 (100). 39 (56); [Found : M+ 153.1154 (El). QH15NO requires M+ 153.11541; Isoxazolidine 7: $1 (250 MHz. CDCl$ 4.74 (lH, t, J 5.3 Hz), 3.60-3.44 (lH, m), 2.00-1.70 (5H, m), 1.55-1.40 (5H, m), 1.30-1.15 (8H, m), 0.86 (3H. t, J7.2 Hz); i$ (100 MHZ, CDCl$ 81.5 (d),
68.0 (q), 61.2 (d), 43.2 (t), 41.7 (t), 36.3 (t), 32.5 (t). 30.1 (t), 25.4 (t), 23.1 (t), 22.7 (t), 14.2 (t), 14.2 (.q): nl/z (E1) 209 (M+, 38 %). 180 (40). 16X (60), 153 (52). 112 (100); [Found : M+ 209.1780 (EI). C~IHZ~NO requires M+ 209.17801; Adalinc 5: SB (400 MHz, CDC13) 3.68-3.64 (lH, m), 2.53 (lH, dd. J 16, 6.6 Hz). 2.37 (2H, 2 coincident d, J 16 Hz), 2.18 (lH, d, J 16 Hz), 1.74-1.60 (5H, m), 1.511.26 (IOH. m). 0.88 (3H. I. J 6.6 Hz); 6(. (l(Hl MHz, CDC13) 211.4 (s), 54.7 (s), 51.6 (t), 49.7 (d), 46.6 (0, 44.7 (t), 36.6 (t). 32.4 (t). 31.6 (t), 22.6 (t), 22.3 (t). 17.9 (t), 14.0 (q); m/z (EI) 209 (M+, 50 a), 180 (22), 166 (86). 153 (100). 110 (68). 96 (78); [Found: M+ 209.1779 (EI). Ct3H23NO requires M+ 209.17 SO)].
Lerrm.
Vol. 36. No. 49. pp 9047.9050, 1995 Elsevier Science Ltd Pnnted in Great Britain 004l~-4039/95 $9.50+0.00
0030-4039~95 10 190% I
A Tandem Synthesis of (k):)-Euphococcinine and (zk))-Adaline Edwin C. Davison and Andrew B. Holmes* l~n~venily Chemical Laboratory. Lensfield Road CAMBRIDGE CB2 IEW, U.K. SmithKline
Beecham
Pharmaceuticals.
Ian New Frontiers
T. Forbes Science Park, Third Avenue,
HARLOW
CM19
5AW. U.K.
Intramolecular hydroxylamine-alkyne cyclisation of the hydroxylamines 8 and 9 afforded sixmembered cyclic nitrones which without isolation undcrwcnt a tandem irmamolecular dipolar cycloaddition to produce the uicyclic isoxazolidines 6 and 7 respectively. These were converted in two steps into the ladybird defence alkaloids (f)-euphoccccinine 4 and (+)-adaline 5
Abstract:
We have previously
described the hydroxylamine-alkyne
cyclisation
of 1 to give the cyclic nitrone 2,
followed by tandem intramolecular dipolar cycloaddition to afford the tricyclic adduct 3 (R = Me) (Schemel),l and we have explored the scope of this cyclisation as a general route to five-, six- and seven-membered cyclic nitrones.? In this Letter the tandem methodology is applied to a concise synthesis of the ladybird defence alkaloids adaline 4 and euphocococcinine 5. TMS
0.
1
Scheme 1 &agenrs
und
Euphococcimnc
2 coditions
: (a) Toluene,
reflux.
I3
3
h (83%)
4 was first isolated from a small sea-coast plant, Euphorbia
aroto Forst.,3 but has
subsequently been found as part of the chemical defence system of both the Australian mealybug ladybird, Cryptdaemus montrouzirri,4 and the Mexican bean beetle. Epilachna varivestis.5 The enantiomerically related alkaloid, adaline 5, also acts as part of the defence system of the European ladybird, Ad& bipunctata, and also has been isolated from Quadrimacukutu Scopoli and P~nrhrrinu L.6 Both alkaloids are proven feeding deterrents to spiders and ants.
9048
A variety of approaches to these alkaloids have been described. 7.8 Both euphococcinine
4 and adaline 5
could be synthesised in racemic form via the tricyclic systems of the type 6 and 7, which could be easily prepared from acyclic hydroxylamines such as 8 and 9 (Scheme 2).
R
R >
Scheme
8; R'= TMS 9; R’ = C4H,
6;R=Me 7; R=C,H,,
(f)-4; R = lie (+)-5; R = C,H,, 2
5Hexyn-l-01 10 was chosen as the starting material for both the natural products. Silylation of the terminal alkyne and the primary alcohol, followed by cleavage of the trimethylsilyl ether gave the alcohol 11 for euphococcinine. Alternatively, formation of 1-tetrahydropyranyloxy-5-hexyne 12, followed by alkylation using butyllithium, tetramethylethylenediamine (TMEDA) and iodobutane, and acetal cleavage afforded the alcohol 13 which served as the key starting compound for adaline.
\%/-OH
TMsboH
a
10
11
c OTHP
F
OH
12 13 Scheme 3 Reagents and conditions: (a) (i) nBuLi, (ii) TMSCl, (iii) HCl aqueous (76%); (b) (i) Dihydropyran, Amberlyst-15 resin, (ii) nBuLi, TMEDA, followed by BuBr (60%); (c) Amberlyst-15. MeOH. Swern oxidation’ of the alcohols 11 and 13 gave the aldehydes 14 and 15 in good yield (Scheme 4). Addition of ally1 magnesium bromide gave the secondary alcohols 16 and 17. Oxidation of the alcohols using C~O~-HOAC,~~ followed by treatment with hydroxylamine hydrochloride in pyridine-ethanol gave the oximes 18 and 19. These were reduced to the corresponding hydroxylamines using sodium cyanoborohydride at pH 3-4. The hydroxylamines were heated to reflux in toluene for 9-12 hours. The resulting nitrones were not isolated, but underwent in situ intramolecu1a.r dipolar cycloaddition to afford the tricyclic adducts 6 and 7.
9049
R’LOH
a
) R’k~O
11; R’=TMS 13; R’=Bu
b 14; R’=TMS 15; R’ = Bu
18; R’=TMS 19; R’=Bu
6;R’=H 7; R’ = Bu
Scheme 4 Reagents rind conditions : (a) Oxalyl chloride, DMSO, Et3N (80-90%); (b) CH2=CHCH2MgBr, ether (70-81%); (c) (i) Cr03, HOAc, (ii) NH2OH.HCl. Py-EtOH (5866%); (d) NaCNBH3. MeOH, pH 3-4; (e) Toluene, reflux, 9 h (7 1.76%). The tricyclic systems were formed in good yield, allowing completion of the syntheses according to the route used by G&singer8 for adaline. Reductive cleavage of the N-O bond, using Raney-nickel and hydrogen, afforded the bicyclic alcohols 20 and 21 in excellent yield. Oxidation of the alcohols with pyridinium chlorochromate gave the required alkaloids (+)-euphococcinine 1 and (+)-adaline 2 respectively, in good yields (Scheme 5).11
R’ dN e H* b-H* a
J
w
HO
6; R’ = H 7; R’ = Bu
Scheme 5 Reagents and conditions:
20; I?‘= H 21; R’= Bu
(a) Raney-Ni. Hz. 90 min (93-96%);
(9-4; (f)-5;
R’ = H R’ = Bu
(b) PCC. CH2Cl2 (70-72%)
Acknowledgements We thank the E.P.S.R.C. for financial support and SmithKline Beechatn Pharmaceuticals for a CASE (ECD). We thank Dr. J. Ballantine (EPSRC Mass Spectrometry Service) for providing mass spectra and Pfizer Central Research (Sandwich) for financial support.
award
9050
References 1. Holmes, A.B.; Smith, A.L.; Williams, S.F.; Hughes, L.R.; Lidert, Z.; Switbenbank, C. J. Org. Chem., 1991, 56. 1393-1405. Fox, M.E.; Holmes. A.B.; Forbes, I.T.; Thompson, M. J. Chem. Sot. Perkin. Trans. 1 1994, 33792. 3395. 3. Hart, N.K.; Johns, S.R.; Lamherton. J.A. AUG. J. Chem. 1967.20, 561-563. Brown, W.V.; Moore, B.P. Ausr. J. Chem. 1982.35. 1255-1261. 4. Eisner, T.; Goetz. M.; Aneshansley, D.; Fetstandig-Arnold, G.; Meinwald, J. Experienta 198642. 2045. 201. 6. 7.
8. 9. 10. 11.
Tursch, B.; Braekman. J.C.; Daloze. D.; Hootele, C.; Losman, D.; Karlsson, R.; Pasteels, J.M. Tetrahedron Let?. 1973. 201-202. Alder. K.; Betzing, H.; Kuth. R.; Dortman, H.H. Liehigs Ann. Chem. 1959,620, 73-87. Hill, R.K.; Renbaum, L.A. Tetrahedron 1982. 3X. 1959- 1963. Gnecco Medina, D.H.; Grierson, D.S.; Husson, H.-P. Tetrahedron Lett. 1983,24, 2099-2102. Yue, C.; Royer, J.; Husson, H.-P. J. Org. Chem. 1992, 57, 4211-4214. G&singer. E.; Witkop, B. Monatsh. Chem. 1980, 111, 803-811. Mancuso. A.J.: Huang, S.L.; Swern, D. J. Org. Chem. 1978,43, 2480-2482. Price, C.C.; Karabinos, J.V. J. Am. C/rem. Sot. 1940.62, 1159-1161. All new compounds exhibited spectroscopic and microanalytical/high resolution mass spectral data in accord with the assigned structure. Selected spectroscopic data: lsoxazolidine 6: 611 (250 MHz, CDCl$ 4.64 (lH, t, J 5 Hz), 3.50-3.39 (lH, m), 1.92-1.79 (lH, m), 1.70-1.50 (4H. m). 1.44-1.22 (5H, m), 1.05 (3H, s); 6~ (100 MHz, CDCl3) 81.7 (d). 65.1 (s), 61.1 (d), 43.2 (t), 35.9 (t), 33.3 (t), 31.4 (q), 25.5 (t), 14.4 (t); m/z (EI) 153 (MH+. 1X’+), 126 (30), 105 (29). 79 (76). 73 (74), 55 (lOO), 41 (98); [Found: M+H+ 154.1232 (EI). CgH15NO requires M+H 154.12321; Euphococcinine 4: ?iB (400 MHz, CDC13) 3.72-3.68 (IH, m), 2.5X (lH, dd, I16, 6.6 Hz), 2.37 (lH, dd, J 16, 2.5 HZ), 2.33 (lH, d, J 16 HZ), 2.23 (lH, d, J 16Hz), 1.76-1.42 (7H. m). 1.19 (3H, s); 6~ (l(H) MHz, CDCl$ 210.5 (s), 53.2 (t), 52.5 (s), 49.8 Cd), 45.9 (0. 38.6 (t), 31.3 (q), 30.9 (q), 17.9 (t); m/i (El) 153 (M+* SC/c), 110 (44), 96 (52), 82 (41), 55 (26), 42 (100). 39 (56); [Found : M+ 153.1154 (El). QH15NO requires M+ 153.11541; Isoxazolidine 7: $1 (250 MHz. CDCl$ 4.74 (lH, t, J 5.3 Hz), 3.60-3.44 (lH, m), 2.00-1.70 (5H, m), 1.55-1.40 (5H, m), 1.30-1.15 (8H, m), 0.86 (3H. t, J7.2 Hz); i$ (100 MHZ, CDCl$ 81.5 (d),
68.0 (q), 61.2 (d), 43.2 (t), 41.7 (t), 36.3 (t), 32.5 (t). 30.1 (t), 25.4 (t), 23.1 (t), 22.7 (t), 14.2 (t), 14.2 (.q): nl/z (E1) 209 (M+, 38 %). 180 (40). 16X (60), 153 (52). 112 (100); [Found : M+ 209.1780 (EI). C~IHZ~NO requires M+ 209.17801; Adalinc 5: SB (400 MHz, CDC13) 3.68-3.64 (lH, m), 2.53 (lH, dd. J 16, 6.6 Hz). 2.37 (2H, 2 coincident d, J 16 Hz), 2.18 (lH, d, J 16 Hz), 1.74-1.60 (5H, m), 1.511.26 (IOH. m). 0.88 (3H. I. J 6.6 Hz); 6(. (l(Hl MHz, CDC13) 211.4 (s), 54.7 (s), 51.6 (t), 49.7 (d), 46.6 (0, 44.7 (t), 36.6 (t). 32.4 (t). 31.6 (t), 22.6 (t), 22.3 (t). 17.9 (t), 14.0 (q); m/z (EI) 209 (M+, 50 a), 180 (22), 166 (86). 153 (100). 110 (68). 96 (78); [Found: M+ 209.1779 (EI). Ct3H23NO requires M+ 209.17 SO)].